Process for preparing cepham compounds

ABSTRACT

Preparing a 3-hydroxy-3-methyl-cepham-4-carboxylic acid, salt or ester in improved yields by heating a penicillin sulfoxide acid, salt, or ester in the presence of sulfuric or sulfamic acid, or a salt or ester thereof in a solvent system containing a tertiary carboxamide.

I United States Patent [151 3,668,202 Foster et al. 1 June 6, 1972 54]PROCESS FOR PREPARING CEPHAM [56] References Cited COMPOUNDS UNITEDSTATES PATENTS [72] Inventors: Bennie J. Foster, Greenwood; Gerald E.

Gutowski; Lowell D. Hatfield, both of I di- 3,275,626 9/1966 Morin et al260/243 C anapolis, all of lnd. 3,507,86l 4/1970 Morin et al ..260/243 C[73] Assignee: Eli Lilly and Company, Indianapolis, Ind. PrimaryExaminer Nicholas S Rizzo [22] Filed; 1970 Attorney-Everet F. Smith andJohn T. Reynolds 21 A 1. No.1 13 815 1 pp 57 ABSTRACT [52 11.8. CI...260/243 C, 424/246, 260/239.1 P p g a y yy p my i i [51] Int, Cl,(207d 99/24, C07d 99/14 salt or ester in improved yields by heating apenicillin sulfox- [58] ide acid, salt, or ester in the presence ofsulfuric or sulfamic Field of Search ..260/243 C acid, or a salt orester thereof in a solvent system containing a tertiary carboxamide.

10 Claims, No Drawings 1 PROCESS FOR PREPARING CEPHAM COMPOUNDSINTRODUCTION BACKGROUND OF THE INVENTION The semi-synthetic productionof 7-acylamidodesacetoxycephalosporin antibiotics from penicillinstarting materials has become of importance recently, due to the processinvention of Morin and Jackson (US. Pat. No. 3,275,626) who describe andclaim a process for converting penicillin sulfoxide esters todesacetoxycephalosporanic acid esters and to the improvements on thatMorin-Jackson process by Chauvette and Flynn who found that certainesters of the penicillin starting materials and of the resultingdesacetoxycephalosporin ester products were more useful in the processin that they were more easily cleaved than those employed by Morin andJackson. Further improvements of the Morin-Jackson process were claimedby Robin D. G. Cooper in application Ser. No. 838,697, filed July 2,1969 who found that the use of certain tertiary carboxamide, urea, orsulfonamide solvents directed the heat rearrangement of the penicillinsulfoxide esters more specifically toward production of thecorresponding desacetoxycephalosporin esters. Some of the 7-acylamidodesacetoxycephalosporanic acid compounds have been found tohave unique properties as antibiotics in their own right. For example,cephalexin, 7-[D-alpha-amino-phenylacetamido]-3-methyl-A-cephem-4-carboxylic acids zwitterion, and pharrnaceutically acceptablecationic and anionic salt forms thereof, are useful as oral antibioticsin combatting infections caused, e.g., by penicillin resistant strainsof Staphylococcus aureus, and many other Gram positive and Gram negativemicro-organisms.

One of the unique advantages of A -desacetoxycephalosporin compounds,that is, compounds of the general formula wherein R is the residue ofthe acylamido group in the 7-position, and R is hydrogen, a salt formingcation, an ester group, or an anionic charge when the COO-- forms a saltwith a cation either within or outside of the molecule, is that suchcompounds can now be prepared from penicillin sulfoxide esters by theMorin-Jackson process, especially as improved by the Chauvette-Flynn andR.D.G. Cooper improvements.

Lowell D. Hatfield in application Ser. No. 799,504, filed Feb. 14, 1969now US. Pat. No. 3,591,585 has disclosed his invention for an improvedprocess for the direct preparation of a desacetoxycephalosporin ester bythe patented Morin- Jackson process as improved by the Cooper solventsystems. Hatfield discovered that by using a combination of a sulfonicacid and a water removal means during the step of heating the penicillinsulfoxide ester starting material, higher yields of the desireddesacetoxycephalosporin esters were obtained. However, small yields ofpreviously unidentified residues were also prepared. One of theinventors herein, G. E. Gutowski, has discovered and claimed in acopending application, Ser. No. 13,814 filed Feb. 24, 1970, certain new3-hydroxy-3-methylcepham-4-carboxylic acids and esters which he hasidentified and characterized. It is now known that these new cephamcompounds were prepared in small yields under the above mentionedHatfield process conditions. When various other acids are used mixturesof products have been obtained.

It is an object of this invention to provide an improved process forpreparing 3-hydroxy-3-methyl-cepham-4-carboxylic acids and esters.

It is a more specific object of this invention to define processconditions which will enable those skilled in the art to prepare 3-hydroxy-3-methylcepham acids, salts, and esters from penicillinsulfoxide acids, salts, and esters in higher yields than has previouslybeen possible.

SUMMARY OF THE lNVENTION Briefly, according to this invention we havediscovered that 3-hydroxy-3-methylcepham-4-carboxylic acids. and esterscan be prepared in high yields by the heat treatment of a correspondingpenicillin sulfoxide acid or ester in the presence of a sulfuric orsulfamic acid or a salt or ester of such an acid in a tertiarycarboxamide containing solvent, at a temperature of from about C. toabout C. for a time sufficient to form the3-hydroxy-3-methylcepham-4-carboxylic acid or ester.

DETAILED DESCRIPTION OF THE INVENTION This invention provides a newprocess for preparing 3- hydroxy-3-methylcepham-4-carboxylic acid andester compounds from the corresponding penicillin sulfoxide acid orester. These products of the process can be described by the formulawhere R is hydrogen, H or an amino protecting group, preferably an acylgroup derived from the penicillin sulfoxide starting material from whichit can be made, and R is hydrogen, an ester group, a salt formingcation, or an anionic charge when R is H For convenience, as indicatedabove these compounds can be referred to generally as 3-hydroxy-3-methylcepham acids, esters, salts, and zwitterions. The term cepham hasbeen defined in the J. Am. Chem. Soc, 84, p. 3,400 1962) as meaning thering structure as an adaptation from the corresponding term penam,defined in J. Amer. Chem. Soc, 75, p. 3,293, footnote 2 (1953) used toname various penicillins and meaning the ring structure An example of aproduct of the process of this invention named by this nomenclaturesystem is 2,2,2-trichloroethyl 3-hydroxy-3-methyl-7-phenoxyacetamido-cepham-4-carboxylate, which can beprepared by heating the penicillin V sulfoxide ester,2,2,2-trichloroethyl,2,2-dimethyl-6-phenoxyacetamidopenam-3-carboxylate-l-oxide, under theconditions set forth herewith. These 3-hydroxy-3 methylcepham-4-carboxylic acid and ester compounds are useful as intermediates for thepreparation of known and new 3-cephem desacetoxycephalosporinantibiotics, e.g., cephalexin, a known antibiotic, by proceduresdescribed hereinbelow. The 3-cephem compounds are related to the cephamcompounds in the bicyclic ring structure with the exception that theformer have a carbon to carbon double bond between the carbon atoms inthe 3 and 4 positions of the dihydrothiazine ring moiety of thestructure. Thus, for example, cephalexin, mentioned above can be named3-methyl-7-(D-a-aminophenylacetamido)-3-cephem-4-carboxylic acid.

According to the process of this invention the penicillin sulfoxideacid, salt or ester is heated in the presence of sulfuric acid, sulfamicacid, or a salt or ester thereof to a temperature of from about 80 C. toabout 150 C. dissolved in a solvent medium containing at least about 10percent by volume of a tertiary carboxamide until an optimum yield ofthe 3-hydroxy- 3-methylcepham-4-carboxylic acid or ester is formed.Generally, the reaction is completed within about 24 hours. Withpreferred solvents and reactants we have obtained good yields of productafter heating the mixture for from 5 to 14 hours. Under the conditionswe prefer to use, the penicillin sulfoxide acid or ester is dissolved toa concentration of from about 1 to about 20 percent by weight in asolvent mixture containing the tertiary carboxamide and organic inertliquid in the optimum proportions of from about 3:5 to about 5:3 partsof volume of the tertiary carboxamide: organic inert liquid. Theproportions of solvent components and concentration of penicillinsulfoxide will vary somewhat, however, with the choice of tertiarycarboxamide, any organic inert liquid, and the selected temperature andtime of reaction. We have found that with the preferred tertiarycarboxamide, N,N- dimethylacetamide (DMA), as the proportion of theorganic inert liquid cosolvent is varied from the proportions givenabove, the yield and nature of the reaction mixture is changed.

Any prior art penicillin or 6-(n-protected-amino)-2,2-dimethylpenam-3-carboxylic acid compound which is not otherwiseconverted under the conditions of acidity and elevated temperatureemployed herein, can be used as a starting material to prepare compoundswithin the scope of this invention. The penicillin or penam must beoxidized to the sulfoxide state prior to treatment. It can also beesterified to protect the carboxyl group in subsequent reactions, butneed not be esterified for preparing the compounds of this invention.Alternatively, the penicillin or penam can be esterified and thenoxidized to the penicillin sulfoxide ester. A wide range of penicillin,and penam compounds can be treated to obtain the3-hydroxy-3-methyl-cepham compounds of this invention. Penicillinssulfoxide salts with alkali metals particularly sodium, potassium,ammonium, and amine salts can also be used but are not necessary.

The amino protection group represented by R in the above formula can beany group known to protect the nitrogen to which it is bonded fromattack by the acid during the heating operation. If R is hydrogen, i.e.,when the nitrogen in the 7- position is in the free amino state, theyields of the desired product are substantially lower. The R group canbe any amino protecting group used to protect amino groups in peptidesynthesis chemistry, e.g., triphenylmethyl, butoxycarbonyl,benzyloxycarbonyl, allyloxycarbonyl, cyclopentyloxycarbonyl, or as ismost practical and preferred, an acyl group. Many acyl groups suitablefor this purpose are already known in the penicillin and cephalosporinantibiotic literature. The preferred amino protecting group is an acylgroup of the forwherein m is an integer of from to 4 inclusive, n is aninteger of from 1 to 4 inclusive, z is 0 or 1, and when z is O, themethylene groups in m and n are connected by a chemical bond, and suchacyl groups substituted on phenyl carbon atoms with fluorine, chlorine,bromine, iodine, hydroxy, C, to

C -alkyl, C, to C -alkyloxy, nitro, cyano, or trifluoromethyl groups.The acyl groups can also have methyl groups in place of l or 2 of thehydrogens on the carbon atoms in the m or n groups. A few representativeexamples of such preferred acyl groups include:

phenylacetyl phenoxyacetyl phenylheptanoyl phenoxyisopropionylbenzyloxyacetyl phenylpropionyl phenylbutyryl 3-methylphenylbutyryl4-propylbenzylacetyl benzyloxyacetyl phenylethoxypropionylphenylbutoxybutyryl 3-fluorophenoxyacetyl 3-hydroxyphenylacetyl4-bromophenylpropionyl 4-iodophenylacetyl 2-chlorobenzyloxypropionylphenyl-a,a-dimethylacetyl 4-nitrophenylacetyl 3-cyanophenylpropionyl4-trifluoromethylphenoxyacetyl, and the like.

Numerous other compounds which form amino protecting groups which can beused in the R position are known in the prior art, e.g., those disclosedin the Behrens et al. U.S. Pat. Nos., 2,479,295 to 2,479,297 and2,562,407 to 2,562,411, and 2,623,876.

The R symbol in the general formula describing the compounds of thisinvention can be hydrogen, a water solubilizing salt such as an alkalimetal, or quaternary amine, or the residue of an ester. The ester groupshould be one which is removable by known methods such as by diluteaqueous base or by the use of trifluoroacetic acid, acetic acid and zincdust, hydrochloric acid and zinc, or the like, or by hydrogenation inthe presence of a hydrogenation catalyst such as a palladium,platinum,or rhodium catalyst on a suitable carrier such as carbon, bariumsulfate, or alumina so that the cephalosporin compound is not degraded.The preferred ester groups are C, to C -tert-alkyl, C to C-tert-alkenyl, C to C -tert-alkynyl such as tert-butyl, tert-pentyl,l,l-dimethyl-2-propenyl, l,ldimethyl-Z-pentynyl, 2,2,2-trichloroethyl,benzyl, 3- or 4- methoxybenzyl, 3- or 4-nitrobenzyl, and Cl-l R" groupswhere R is C, to C, alkanoyl, benzoyl, toluoyl, thenoyl, or furoyl aswell as benzhydryl, as set forth in the U.S. Pat. No. 3,284,451, orbenzhydryl and the like.

Compounds of this invention where R is hydrogen, can be obtained afterthe penicillin sulfoxide rearrangement reaction has been completed andare formed by subjecting the 3-hydroxy-3-methyl-7-acylamidocepham-4-carboxylic acid or ester to theaction of phosphorus pentachloride in the presence of an equivalentamount of a tertiary amine such as pyridine, followed by a loweralkanol, e.g., methanol, and then by water to cleave the 7-acyl group.Examples of such a product are3-hydroxy-3-methyl-7-aminocepham-4-carboxylic acid and tert-butyl3-hydroxy-3-methyl-7-aminocepham-4- carboxylate. Such compounds can berecovered from their reaction mixtures by conventional methods, e.g., asa salt with a C to c -hydrocarbonsulfonic acid which salt precipitatesfrom most organic solvents. These 7-amino compounds also form inner orzwitterionic salts with the 4-carboxyl group (in which event R is ananionic charge). In such cases R can represent the H moiety where thesecond hydrogen is supplied by the carboxyl. Such compounds also formsalts with strong acids having a pKa of less than 4 such ashydrochloric, sulfuric, orthophosphoric, nitric, iodic, perchloric acidsand the like. If desired 6-aminopenam-3-carboxylic acid such as 6-aminopenicillanic acid (6-APA), and esters thereof such as2,2,2-trichloroethyl 6-amino-2,2-dimethylpenam-3-carboxylate can beconverted by the process of this invention to the corresponding 7-amino3-hydroxy-3-methylcepham-4-carboxylate acid, or ester, but it ispreferred to use a penam in which the amino group is protected asindicated above.

Contrary to the requirements of the above mentioned Hat field improvedprocess, it is not necessary to remove water from the reaction mixtureduring the heating operation of this improved process. The tertiarycarboxamide may be used as the only solvent system, but for optimumyields it will often be desirable to dilute the tertiary carboxamidewith an inert organic liquid. In this process, it is not necessary tochoose the inert organic liquid on the basis of whether or not it formsan easily removed azeotrope with water, as was desirable in the Hatfieldprocess. However, those same organic liquids can also be used asdiluents for the tertiary carboxamide solvent in this process. Thus, theinert organic liquids can be exemplified by hydrocarbons, especially Cto C -alkanes and C to C,,-ar0- matic hydrocarbons, halogenatedhydrocarbons, particularly those containing from one to six carbon atomsand from one to four chlorine or bromine atoms, as well as ethers,esters, and the like, as set forth in various chemistry handbooks, e.g.,Handbook of Chemistry, edited by N. A. Lange, Ninth Edition (1956),published by Handbook Publishers, Inc., Sandusky, Ohio, pp. 1,484 to1,486, and 1,493,and in the Chemical Rubber Co., Handbook of Chemistryand Physics, 45th Edition, pp. D-l to D-18'(1964-65). Examples ofsuitable diluents include pentane, hexane, heptane, benzene, toluene,xylene, methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, methyl ethyl ketone, methyl isobutyl ketone, ethylacetate, isopropyl acetate propylene glycol diacetate, acetonitrile,propionitrile, dioxane, and the like. As indicated above the tertiarycarboxamide should constitute at least about 10 percent by volume of thereaction mixture. The diluting organic liquid or liquids forms theremainder of the solvent system.

The general types of tertiary carboxamides which can be used have thestructural formula wherein l. R, is hydrogen, and each of R and R,, isalkyl, phenyl, tolyl, or xylyl such that R, and R together contain up toabout 14 carbon atoms;

2. at least one of R,, R and R,, is alkyl, and not more than two of R,,R and R,, are phenyl, tolyl, xylyl, and R,, R and R together contain upto about 18 carbon atoms;

3. R, is hydrogen or alkyl, R and R,, are taken together with thenitrogen to which they are bonded to form a saturated monocylic ringwhich contains from four to six carbon atoms in the ring, which ring canalso contain an oxygen ring member, gamma to the ring nitrogen, and R,,R and R together contain not more than 12 carbon atoms; and/or 4. R, andR are taken together with the amide grouping to which they are bonded toform a saturated carbonyl containing monocylic ring having from four tosix ring carbon atoms, R, is alkyl, phenyl, tolyl, or xylyl, and R,, Rand R,, together contain not more than 14 carbon atoms.

Examples of tertiary carboxamides of the types described above, whichmay be used in the process include:

1. N,N-dimethylformamide (DMF), N,N-diethylformamide,N,N-diisopropylformamide, N,N-dibutylformamide, N,N- dipentylformamide,N-methyl-N-ethylformamide, N-methyl- N-phenylformamide, N-ethyl-N-(m-tolyl) formamide, N- propyl-N-(3,5-dimethylphenyl)formamide, N ,N-diphenylformamide, N,N-bis (4-methylphenyl) formamide,N,(3,5- dimethyl)-N-methylformamide, N,N bis (2,4-dimethylphenyl)formamide, and the like.

2. N,N-dimethylacetamide (DMA), N,N-diethylacetamide,N,N-diisopropylacetamide, N,N-dibutylacetamide,N,N-ditert-butyl-acetamide, N,N-dimethylpropionamide, N,N-diethylpropionamide, N,N-dipentylpropionamide, N,N- dimethylbutanamide,N,N-diethylbutanamide, N,N-dimethyldecanamide, N,N-dimethylbenzamide,N,N-diethylbenzamide, N,N-dipropyl-m-toluamide, N,N-dibutyl-p-toluamide,N-phenyl-N-methylacetamide, N-(p-tolyl)-N-ethylacetamide, N-( 3,5dimethylphenyl)-N-methylpropionamide, N,N-dimethyl-3,S-dimethylbenzamide, N,N-dibutyl-4-ethylbenzamide,N,N-diphenylacetamide, N-(3-methylphenyl)-N-ethylbenzamide,N,N-bis(6-methylphenyl) propionamide, N ,N- bis(3,5-dimethylphenyl)propionamide, and the like;

3. N-formylpiperidine, N-acetylpyrrolidine, N-propionylmorpholine,N-acetyl-4,5-dimethylpyrrolidine, N-butanoylpiperidine,N-acetyl-6-methylpiperidine, and the like; and

4. l-methyl-2-pyrrolidone, l-phenyl-2-pyrrolidone, l-butyl-2-piperidone, l-pentyl-2-piperidone, l -(m-tolyl )-2- piperidone,l-ethyl-2-pipen'done, l-(3,5-dimethylphenyl)-2- piperidone,l-methyl-2-piperidone, l-phenyl-Z-piperidone, 1- propyl-2-piperidone, l-isopropyl-2-pyrrolidone, 1 3- methylphenyl)-2-pyrrolidone,N-methyl-Z-homopiperidone, N-ethyl-Z-homopiperidone. However, weespecially prefer to use dimethylacetamide, dimethylformamide, orN-methyl-Z- pyrrolidone in this heating step.

The acid compounds used for preparing the 3-hydroxy-3- methylcephamproducts of the process of this invention include sulfuric acid orsulfamic acid, and salts and esters of such acids. Examples of salts ofthese acids include the alkali metal salts, e.g., the lithum, sodium,potassium, and rubidium salts, although only the sodium and potassiumsalts are of practical economic significance. The magnesium and calciumsalts of these acids may also be used but are not preferred. Partial andcomplete esters of these acids with C, to C -alkanols such asdimethylsulfate, diethylsulfate, dimethylsulfamate, dipropylsulfamateand the like can also be used. However, it is easier and more convenientto use the free acids in the reaction mixture.

The concentration of the sulfuric acid, sulfamic acid, or equivalentsalts, or ester in the reaction mixture will vary depending upon thenature of the acid substance, the concentration of the penicillin orpenam sulfoxide ester, the solvent system used, the desired time andtemperature of reaction, and the like. In general, the molar ratio ofpenicillin sulfoxide to acid ranges from about 1:1 to about 50:1.Preferably a molar ratio of penicillin sulfoxide ester to acid rangesfrom about 5:1 to about 15:1. Theconcentration of the penicillinsulfoxide ester in the total solvent system can vary extensively butpreferably constitutes from about 1 to about 20 percent by weight of thereaction mixture.

The penicillin or penam sulfoxide acid, salt, or ester in the acidifiedsolvent system, is heated to from about C. to about 150 C. to direct therearrangement of the penicillin sulfoxide ester to the3-hydroxy-3-methylcepham compound. In the preferred tertiary carboxamidecontaining solvents or solvent mixtures, the preferred heatingtemperature is from about C. to about C. for from about 2 to about 24hours. Lower temperatures require more time, while at highertemperatures the reaction mixture tends to produce a more complexreaction product.

The 3-hydroxy-3-methylcepham ester products can be recovered from thereaction mixture by conventional methods. Usually the reaction mixtureis concentrated under vacuum to remove most of the reaction mixturesolvents therefrom. The residue is dissolved in a suitable organicsolvent such as a chlorinated hydrocarbon solvent such as methylenechloride, chloroform, carbon tetrachloride, a C, to C -alkanol such asmethanol, isopropanol, etc., or a hydrocarbon such as benzene, toluene,xylene, heptane, or the like, and extracted with dilute aqueous acids toremove residual tertiary carboxamide solvents. The organic solventsolution containing the product can be concentrated to obtain relativelypure product, sufficiently pure for further contemplated reactions, orfurther purified by conventional methods, e.g., re-crystallization.

Examples of compounds of this invention and the sulfoxides from whichthey can be obtained include the following:

tert-Butyl 3-hydroxy-3-methyl-7-(phenylacetamido) cepham-4-carboxylatefrom the tert butyl ester of phenylmethylpenicillin sulfoxide.

l, l-Dimethyl-Z-propynyl 3-hydroxy-3-methyl 7-(4-nitrophenylacetamido)cepham-4-carboxylate from the 1,1-dimethyl-Z-propynyl ester of 4'-nitrophenylmethyl penicillin sulfoxide,

2,2,2-trichloroethyl 3-hydroxy-3-methyl-7-(octanoylamido-)cepham-4-carboxylate from the 2,2,2-trichloroethyl ester ofheptylpenicillin sulfoxide,

4-Nitrobenzyl3-hydroxy-3-methyl-7-(a,a-dimethylphenylacetamido)cepham-4-carboxylatefrom the 4-nitrobenzyl ester of a,a-dimethylphenylmethyl-penicillinsulfoxide,

tert-Butyl 3-hydroxy-3-methyl-7-( 5-butoxycarbonylaminoadipoylamido)cepham-4-carboxylate from thetert-butyl ester of the N-butoxycarbonyl protected penicillin Nsulfoxide,

3-Hydroxy-3-methyl-7-(phenoxyacetamido-)cepham-4-carboxylic acid fromphenoxymethyl penicillin sulfoxide,

3-l-lydroxy-3-methyl-7-(2'-thienylacetamido)cepham carboxylic acid fromthienylmethylpenicillin sulfoxide.

Salts of such compounds are made by treating the acids with anappropriate base or basic salt such as sodium hydroxide, potassiumhydroxide, sodium acetate, potassium hydroxide, potassium carbonate andthe like to form the sodium or potassium salts, or with ammoniumhydroxide or a trialkylamine such as trimethylamine or triethylamine toform the respective ammonium or amine salts.

The products of the process of this invention show some antibioticactivity against various Gram positive and Gram negative bacteria. Theyare of primary interest for use in preparing compounds having the A-cephem cephalosporin nucleus. For example, stirring one of the3-hydroxy-3-methyl-cepham compounds in a mixture of acetic anhydride andN,N- dimethylacetamide in an oil bath for approximately minutes at aboutlO0-l10 C. gives good yields of the corresponding 3-methyl-A -cephemcompound. For example, tert-butyl3-hydroxy-3-methyl-7-(phenoxyacetamido)cepham-4-carboxylate will undergoan elimination reaction to form the corresponding ester, tert-butyl 3-methyl -7-(phenoxyacetamido)-A -cephem-4-carboxylate, which is useful inthe overall process of making the known cephalosporin antibiotic,cephalexin [7-D-(a-aminophenylacetamido)-3-methyl-A -cephem-4-carboxylicacid] from phenoxymethyl penicillin. In such process, the phenoxyacetylgroup is cleaved by treatment of the 3-methyl-A -cephem ester withphosphorus pentachloride and pyridine, followed by treatment of thechlorinated product with methanol, and then with water to form the7-amino-3 -methyl-A -cephem nucleus ester which can be recoveredconveniently, for example, as the p-tolenesulfonate salt, followed byreacylation of the nucleus ester with an activated or reactive form ofan N-protected a-aminophenylacetic acid, followed by removal of theN-protecting group and the ester group to obtain cephalexin.

The invention is further exemplified by the following detailed examples,in which all temperatures are in degrees centigrade.

EXAMPLE 1 4-Nitrobenzyl 3-hydroxy-3-methyl-7-(2-phenoxyacetamido)cepham-4-carboxylate (ll).

A solution of 500 mg. of penicillin-V-sulfoxide pnitrobenzyl ester, 10mg. p-toluene sulfonic acid monohydrate and 142 mg. dimethylacetylenedicarboxylate in 10 ml. N,N- dimethylacetamide were stirred in an oilbath at l l0-l 13 for 5 hours. The majority of solvents were removed invacuo and the oily residue passed over 8 g. Floricil, eluting withchloroform. The concentrated eluate was taken up in hot ethanol fromwhich mg. (17.2 percent) of 4-nitrophenyl 3- methyl 7-(2-phenoxyacetamido )-3-cephem-4-carboxylate (111) were deposited uponcooling, m.p. l90-l9l. Mother liquors were evaporated and the residuetriturated with hot methyl isobutyl ketone to afford a white solid,recrystallization of which from hot acetonitrile yields 64 mg. 12.8percent) of the title compound (11), m.p. 2 l42l5.

During repetitions of this preparation yields of 11 varied between 10and 22 percent.

The structure of compound II, 4-nitrobenzyl 3-hydroxy-3-methyl-7-(2-phenoxyacetamido)cepham-4-carboxylate was furthercharacterized by preparation by known methods of a.3-hydroxy-3-methyl-7-(2'-phenoxyacetamido)cepham-4- carboxylic acid b.methyl B-hydroxy -7-(2-phenoxyacetamido)cepham-4- carboxylate c.4-nitrobenzyl 3-(trimethylsilyloxy)-3-methylphenoxyacetamido)cepham-4-carboxylate d. 4-nitrobenzyl3-acetoxy-3-methyl-7-(2-phenoxyacetamido)cepham-4-carboxylate e.4-nitrobenzyl 3-( trifluoroacetoxy)-3-methyl-7- 2phenoxyacetamido)cepham-4-carboxylate f. 4-nitrobenzyl3-hydroxy-3-methyl-7-( 2 pheno xya cetamido)cepham-4-carboxylatel -oxideg. 4-nitrobenzyl 3-acetoXy-3-methyl-7-(2'phenoxya cetamido)cepham-4-carboxylatel -oxide h. 4-nitrobenzyl3-acetoxy-3-methyl-7(n-acetyl-2'-phenoxyacetamido)cepham-4-carboxylatel-oxide i. 4-nitrobenzyl 3-hydroxy-3-methyl-7-( 2'-phenoxyacetamido)cepham-4-carboxylatel 1 -dioxide j. 4-nitrobenzyl3-acet0Xy-3-methyl-7-(2-phenoxyacetamido)cepham-4-carboxylatel l-dioxideSpectral data and elemental analyses were in agreement for the abovenamed compounds, and this provided further evidence of the correctnessof the named compound 11, namely, 4-nitrobenzyl 3-hydroxy-3-methyl-7-( 2-phenoxyacetamido)cephem-4-carboxylate.

EXAMPLE 2 This example illustrates the utility of the new compounds asintermediates in the preparation of the corresponding 3- methyl-3-cephemcompounds.

A suitable vessel containing a mixture of mg. of 4- nitrobenzyl3-hydroxy-3-methyl-7-( 2 -phenoxyacetamido)cepham -4-carboxylate in 1ml. of acetic anhydride and 0.2 ml. of N,N-dimethylacetamide (DMA) wasimmersed in an oil bath, and the mixture was stirred for approximately15 minutes at C. From this reaction mixture there is obtained4-nitrobenzyl 3-methyl-7-(2-phenoxyacetamido)-3-cephem-4-carboxylate,which upon ester group removal by known hydrogenation methods can beconverted to 3-methyl-7-(2-phenoxyacetamido)-3-cephem-4- carboxylate, aknown antibiotic.

EXAMPLE 3 This example illustrates the direct preparation of the 3-hydroxy-B-methyl eepham compound in the acid form.

A solution containing 10.0 g. of penicillin V sulfoxide [2,2-dimethyl-6-phenoxyacetamido penam-S-carboxylic acid- 1 -oxide], 0.15 ml.of concentrated sulfuric acid, 100 ml. of benzene, and 75 ml. of N,N-dimethylacetamide was refluxed 14 hours. The dark red coloredreaction mixture was then concentrated under vacuum and the residue wasdissolved in 200 ml. of methylene chloride. After washing with dilutehydrochloric acid solution to remove residual N ,N- dimethylacetamide,the methylene chloride solution was extracted with 5 percent disodiumhydrogen orthophosphate in water solution. Acidification of the aqueousphase, extraction with chloroform, and concentration of the chloroformsolution left 4.7 g. (47 percent yield) of the acid, 3-hydroxy-3-methyl-7-(phenoxyacetamido)cepham-4-carboxylic acid. An analyticalsample was obtained by recrystallization from chloroform, m.p. l52l53 C.The acid product was also characterized by infrared (IR), ultraviolet(UV), and nuclear magnetic resonance (NMR) spectra, elemental analysis,and non-aqueous titration.

EXAMPLE 4 A 10.0 g. portion of 4-nitrobenzyl penicillin V sulfoxideester was added to 80 ml. of benzene and 60 ml. of DMA containing 2drops of concentrated sulfuric acid. The solution was refluxed for 12hours and then concentrated to a residue weight of 23.2 g. Addition of100 ml. of isopropyl alcohol resulted in direct crystallization ofsubstantially pure 4- nitrobenzyl3-hydroxy-3-methyl-7-phenoxyacetamidocepham-4-carboxylate. A purifiedsample of this product had a melting point of 2 l 2-2 1 4 C. It wasfurther characterized by IR, UV, NMR spectral analyses, as well as byelemental analysis and thin layer chromatographic (TLC) methods. Alldata were consistent with the assigned structure for the named compound.

EXAMPLE 5 The procedure of Example 4 was repeated but employing anequivalent amount of the dimethyl sulfate ester in place of sulfuricacid. The product, 4nitrobenzyl 3-hydroxy-3methyl-7-(phenoxyacetamido)cepham-4-carboxylate had a melting point of 208-2 C.

EXAMPLE 6 A mixture of 10.0 g. of penicillin V sulfoxide, 4-nitrobenzylester, 0.194 g. of sulfamic acid in l 12 ml. of benzene and 88 ml. ofdimethylacetamide was stirred and refluxed 14 hours and then allowed tostand at room temperature for 3 hours. The solvents were removed undervacuum. The residue was triturated with xylene and re-concentrated undervacuum. The product was triturated with chloroform and the crystallineproduct was filtered. It weighed 3.91 g. (40.5 percent yield), mp. 21l-2l2 C. with decomposition.

- EXAMPLE 7 A mixture of 2.5 g. of 4-nitrobenzyl penicillin V sulfoxideester, 0.07 g. of potassium bisulfate, in 28 ml. of benzene and 22 ml.of dimethylacetamide was refluxed until no starting material was present(about 18 hours). The mixture was concentrated in vacuo andre-concentrated after washing with xylene. The product 4-nitrobenzyl3-hydroxy-3-methyl-7- (phenoxyacetamido)cepham-4-carboxylate, wascrystallized after triturating with chloroform. The product weighed 1.02g. (41 percent yield) mp. 21 l-2l3C. A mixed melting point with a knownsample of the same product was 21 l2 l 3C.

EXAMPLE 8 The procedure of Example 4 is repeated using 2,2,2-trichloroethyl penicillin G sulfoxide ester in a mixture of benzene anddimethylacetamide containing concentrated sulfuric acid as theacidifying agent. After refluxing, and work-up of the reaction mixturethere is obtained a product, 2,2,2- trichloroethyl3-hydroxy-3methyl-6-(phenylacetamido)cepham-4-carboxylate.

This ester is useful as our intermediate in the manufacture ofdesacetoxycephalosporin antibiotic substances, e.g., cephalexin.

EXAMPLE 9 The procedure of Example 4 is repeated except that tertbutyl2,2-dimethyl-6-( a,a-dimethyl-phenylacetamido )penam-3-carboxylate-l-oxide is used as starting material in place of the4-nitrobenzyl penicillin V sulfoxide ester. There is obtained as productthe tert-butyl3-h'ydroxy-3-methyl-7-(a,adimethylphenylacetamido)cephamA-carboxylate.

This ester is useful as an intermediate in the production ofdesacetoxycephalosporin antibiotic substances.

EXAMPLE l0 The procedure of Example 4 is repeated except that 1,1-dimethyl-Z-propynyl 2,2-dimethyl-6-(2'-thienylacetamido)penam-4-carboxylatel-oxide is used in place of thepenicillin V sulfoxide ester. There is obtained as product thel,l-dimethyl-2-propynyl 3-hydroxy-3-methyl-7-(2'-thienylacetamido)cepham-4-carboxylate.

This ester is useful as an intermediate in the production ofdesacetoxycephalosporin antibiotic substances such as 3-methyl-7-(2'-thienylacetamido)-A"-cephem-4-carboxylic acid, a knownantibiotic.

EXAMPLE It In a solution of dry benzene containing 28 millimoles of drypyridine there are dissolved 7.8 millimoles of 4-methoxybenzyl3-hydroxy-3-methyl-7-(phenoxyacetamido)cepham- 4-carboxylate, which hasbeen prepared by heating the 4- methoxybenzyl penicillin V sulfoxideester in dimethylacetamide to l 10 C. for about 6 hours with sulfuricacid catalysis. The resulting solution is warmed to 50 to 60C. and thenwhile stirring 28 millimoles of phosphorus pentachloride are added atone time. The mixture is stirred at this temperature under a nitrogenatmosphere for about 1 hour. The resulting mixture is then cooled to 0to 5C. and treated with an excess of methanol. This methanol-treatedmixture is stored for several hours at room temperature. After removingmost of the benzene and methanol solvents by evaporation below 50C.under reduced pressure, the residue (having a pH of about 1.8) is takenup in a 1:1 by volume mixture of water and tetrahydrofuran. After 2hours, the tetrahydrofuran is removed and the aqueous residue is stirredwith ethyl acetate and adjusted to pH 6.5-7 with l N aqueous sodiumhydroxide. The ethyl acetate layer containing the crude 4-methoxybenzyl3-hydroxy-3-methyl-7-aminocepham-4-carboxylate ester product is treatedwith about 8 millimoles p-toluene sulfonic acid to precipitate thepmethoxybenzyl 3-hydroxy-3-methyl-7 -amino-cepham-4-carboxylatep-toluene sulfonate salt, which is separated from the reaction mixtureby filtration. The separated salt can be stored in salt form or taken upin ethyl acetate/water mixture and adjusted to near pH 7 to separate thepure p-methoxybenzyl 3-hydroxy-3-methyl-7-amino cepham-4-carboxylate.

This ester product can be used as an intermediate, e.g., to preparecephalexin by acylating the amino-ester with N-(tertbutoxycarbonyl)D-a-phenylglycine in the mixed anhydride reaction, heating the acylatedester in N,N-dimethylacetamide containing acetic anhydride to about C.,and then treating the resulting product with anhydrous trifluoroaceticacid for 5 minutes to obtain 3-methyl-7-(D-a-aminophenylacetamido)-A-cephem-4-carboxylic acid (cephalexin). This antibiotic compound can beadministered topically, parenterally, or as is preferred, orally indoses of from about 50 mg. to about 500 mg., from one to four times perday depending upon the disease condition being treated.

EXAMPLE 12 Following the procedure of Example 3, phenoxymethylpenicillin sulfoxide acid is mixed in N,N-dimethylacetamide and benzenesolvent with an equivalent amount of sulfamic acid and heated for 14hours. After concentration of the reaction mixture and purificationaccording to the procedures described therein, there is obtained asproduct, 3-hydroxy-3- methyl-7-( phcnoxy-acetamido )cepham-4-carboxylicacid.

We claim:

1. A process which comprises heating a penicillin sulfoxide acid orester in the presence of sulfuric acid, sulfamic acid, an alkali metalsalt or an ester of sulfuric or sulfamic acid with a C to C -alkanolthereof, to from about 80 C. to about C. in a reaction mixturecontaining at least about 10 percent by volume of a tertiarycarboxamide, said tertiary carboxamide being further defined as havingthe formula wherein R, is hydrogen, and each of R, and R alkyl, phenyl,tolyl, or xylyl such that R and R together contain up to about 14 carbonatoms;

2. at least one of R R and R alkyl, and not more than two of R R and Rare phenyl, tolyl, xylyl, and R R and R together contain up to about 18carbon atoms;

. R is hydrogen or alkyl, R and R are taken together with the nitrogento which they are bonded to form a saturated monocyclic ring whichcontains from four to six carbon atoms in the ring, which ring can alsocontain an oxygen ring member, gamma to the ring nitrogen, and R R and Rtogether contain not more than 12 carbon atoms; and/or 4. R and R aretaken together with the amide grouping C(O)N) to which they are bondedto form a saturated carbonyl containing monocyclic ring having from fourto six ring carbon atoms, R;, is alkyl, phenyl, tolyl, or xylyl, and R Rand R together contain not more than 14 carbon atoms;

to form as product a 3-hydroxy-3-methylcepham-4-carboxylic acid orester.

2. A process as defined in claim 1 wherein a penicillin sulfoxide esteris heated in the presence of sulfuric acid to from about 90 C. to about120 C. in a reaction mixture containing a tertiary carboxamide whereineach of R R and R is alkyl, such that R,, R and R together contain up toabout 18 carbon atoms.

3. A process as defined in claim 2 wherein a penicillin sulfoxide esteris heated in the presence of sulfuric acid in N,N- dimethylacetamide.

4. A process as defined in claim 2 wherein 4-nitrobenzylphenoxymethylpenicillin sulfoxide ester is heated in the presence ofsulfuric acid in a mixture of N,N-dimethylacetamide and benzene to form4-nitrobenzyl 3-hydroxy-3-methyl7-(phenoxyacetamido)cepham-4-carboxylate.

5. A process as defined in claim 1 wherein a penicillin sulfoxide acidis heated in the presence of sulfuric acid in a reaction mixturecontaining a tertiary carboxamide of the indicated formula wherein eachof R R and R is alkyl, such that R R and R together contain up to about18 carbon atoms.

6. A process as defined in claim 5 wherein phenoxymethyl penicillinsulfoxide acid is heated in the presence of sulfuric acid inN,N-dimethylacetamide.

7. A process as defined in claim 1 wherein a penicillin sulfoxide esteris heated in the presence of sulfamic acid to from about C to about C ina reaction mixture containing a tertiary carboxamide of the formula inclaim 1 wherein each of R R and R is alkyl, such that R,, R and Rtogether contain up to about 18 carbon atoms.

8. A process as defined in claim 7 wherein 4-nitrobenzyl phenoxymethylpenicillin sulfoxide ester is heated in the presence of sulfamic acid insolvent system containing N,N- dimethylacetamide.

9. A process as defined in claim 1 wherein a penicillin sulfoxide acidis heated in the presence of sulfamic acid in a solvent mediumcontaining a tertiary carboxamide of the indicated formula wherein eachof R R and R is alkyl such that R R and R together contain up to about18 carbon atoms.

10. A process as defined in claim 8 wherein phenoxymethyl penicillinsulfoxide acid is heated in the presence of sulfamic acid in a solventsystem containing N,N-dimethylacetamide.

2. at least one of R1, R2, and R3 alkyl, and not more than two of R1,R2, and R3 are phenyl, tolyl, xylyl, and R1, R2, and R3 together containup to about 18 carbon atoms;
 2. A process as defined in claim 1 whereina penicillin sulfoxide ester is heated in the presence of sulfuric acidto from about 90* C. to about 120* C. in a reaction mixture containing atertiary carboxamide wherein each of R1, R2, and R3 is alkyl, such thatR1, R2, and R3 together contain up to about 18 carbon atoms.
 3. Aprocess as defined in claim 2 wherein a penicillin sulfoxide ester isheated in the presence of sulfuric acid in N, N-dimethylacetamide.
 3. R1is hydrogen or alkyl, R2 and R3 are taken together with the nitrogen towhich they are bonded to form a saturated monocyclic ring which containsfrom four to six carbon atoms in the ring, which ring can also containan oxygen ring member, gamma to the ring nitrogen, and R1, R2, and R3together contain not more than 12 carbon atoms; and/or
 4. A process asdefined in claim 2 wherein 4-nitrobenzyl phenoxymethylpenicillinsulfoxide ester is heated in the presence of sulfuric acid in a mixtureof N,N-dimethylacetamide and benzene to form 4-nitrobenzyl3-hydroxy-3-methyl 7-(phenoxyacetamido)cepham-4-carboxylate.
 4. R1 andR2 are taken together with the amide grouping (-C(O)-N-) to which theyare bonded to form a saturated carbonyl containing monocyclic ringhaving from four to six ring carbon atoms, R3 is alkyl, phenyl, tolyl,or xylyl, and R1, R2, and R3 together contain not more than 14 carbonatoms; to form as product a 3-hydroxy-3-methylcepham-4-carboxylic acidor ester.
 5. A process as defined in claim 1 wherein a penicillinsulfoxide acid is heated in the presence of sulfuric acid in a reactionmixture containing a tertiary carboxamide of the indicated formulawherein each of R1, R2, and R3 is alkyl, such that R1, R2, and R3together contain up to about 18 carbon atoms.
 6. A process as defined inclaim 5 wherein phenoxymethyl penicillin sulfoxide acid is heated in thepresence of sulfuric acid in N,N-dimethylacetamide.
 7. A process asdefined in claim 1 wherein a penicillin sulfoxide ester is heated in thepresence of sulfamic acid to from about 90* C to about 120* C in areaction mixture containing a tertiary carboxamide of the formula inclaim 1 wherein each of R1, R2, and R3 is alkyl, such that R1, R2, andR3 together contain up to about 18 carbon atoms.
 8. A process as definedin claim 7 wherein 4-nitrobenzyl phenoxymethyl penicillin sulfoxideester is heated in the presence of sulfamic acid in solvent systemcontaining N,N-dimethylacetamide.
 9. A process as defined in claim 1wherein a penicillin sulfoxide acid is heated in the presence ofsulfamic acid in a solvent medium containing a tertiary carboxamide ofthe indicated formula wherein each of R1, R2, and R3 is alkyl such thatR1, R2, and R3 together contain up to about 18 carbon atoms.
 10. Aprocess as defined in claim 8 wherein phenoxymethyl penicillin sulfoxideacid is heated in the presence of sulfamic acid in a solvent systemcontaining N,N-dimethylacetamide.